research article open access safety and effectiveness ......in vitro studies suggest that the...

RESEARCH ARTICLE Open Access

Safety and Effectiveness of two treatment regimeswith tranexamic acid to minimize inflammatoryresponse in elective cardiopulmonary bypasspatients: a randomized double-blind, dose-dependent, phase IV clinical trialJuan J Jiménez1*, José L Iribarren1, Maitane Brouard1, Domingo Hernández2, Salomé Palmero1, Alejandro Jiménez3,Leonardo Lorente1, Patricia Machado4, Juan M Borreguero5, José M Raya4, Beatriz Martín5, Rosalía Pérez1,Rafael Martínez6 and María L Mora1

Abstract

Background: In cardiopulmonary bypass (CPB) patients, fibrinolysis may enhance postoperative inflammatoryresponse. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA)reduced CPB-mediated inflammatory response (IR).

Methods: We performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPBpatients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPBand placebo after CPB) or the double-dose group (40 mg/Kg TA before and after CPB).

Results: 160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030). After adjusting for hypertension, totalprotamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83), (P = 0.013)]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12). The double-dose group had significantlylower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949) mL; P = 0.01 corrected-Psignificant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09) vs. 0.20(95 CI: 0.05-0.35) after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant].We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P < 0.01), D-dimer (rho = 0.24; P <0.01), norepinephrine (rho = 0.33; P < 0.01), troponin I (rho = 0.37; P < 0.01), Creatine-Kinase (rho = 0.37; P < 0.01), CreatineKinase-MB (rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P < 0.01) at ICU arrival. Two patients (1.3%) had seizure, 3patients (1.9%) had stroke, 14 (8.8%) had acute kidney failure, 7 (4.4%) needed dialysis, 3 (1.9%) suffered myocardialinfarction and 9 (5.6%) patients died. We found no significant differences between groups regarding these events.

Conclusions: Prolonged inhibition of fibrinolysis, using an additional postoperative dose of tranexamic acid reducesinflammatory response and postoperative bleeding (but not transfusion requirements) in CPB patients. A questionwhich remains unanswered is whether the dose used was ideal in terms of safety, but not in terms of effectiveness.

Current Controlled Trials number: ISRCTN: ISRCTN84413719

Keywords: Cardiac surgery, Cardiopulmonary bypass, Fibrinolysis, Tranexamic acid, Inflammatory response, Bleeding

* Correspondence: [email protected] Care Department. Hospital Universitario de Canarias. Ofra s/n, LaCuesta. 38320-La Laguna. EspañaFull list of author information is available at the end of the article

Jiménez et al. Journal of Cardiothoracic Surgery 2011, 6:138http://www.cardiothoracicsurgery.org/content/6/1/138

© 2011 Jiménez et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.

http://www.controlled-trials.com/ISRCTN84413719mailto:[email protected]://creativecommons.org/licenses/by/2.0

BackgroundExcessive bleeding and inflammatory response (IR) aftercardiopulmonary bypass (CPB) are common complica-tions of cardiac surgery [1]. Although tranexamic acid(TA), a lysine analog competitive inhibitor of plasminand plasminogen [2], is effective in reducing bleedingafter cardiac surgery, its anti-inflammatory effect infibrinolysis blockade has been less studied.In vitro studies suggest that the exposure of D-dimer

fragments to monocytes initiates the synthesis and releaseof IL-6 [3]. Excessive plasmin activity and/or D-dimer for-mation may play an important role in proinflammatorycytokine and cellular response activation during CPB [4].In patients undergoing elective CPB, prophylactic blockadeof fibrinolysis decreases molecular expression of IR [5].This IR may contribute to postoperative complications,including myocardial dysfunction, respiratory failure, renaland neurologic dysfunction, bleeding disorders, alteredliver function, and ultimately, multiple organ failure(MOF) [4]. In a previous study using TA before and afterCPB we observed reduced bleeding and IR [6]. Theseresults were encouraging but left unanswered the questionof whether the postoperative dose, coinciding with greatestfibrinolytic activation, was determinant in decreasing post-operative IR and bleeding. Nevertheless newer data indi-cate that, in a dose-dependent fashion, TA is associatedwith an increase of adverse events, particularly the obser-vation of seizures [7]. The incidence of this adverse effectvaries from 2.7% to 4.6% in any major surgical procedure,independently of dosing schedule [8-10]. For this reason,we also focused on the safety profile of TA dosing sche-dule as a part of the study.

MethodsThe study was approved by our university hospital ethicscommittee and conducted according to the HelsinkiDeclaration. We report this trial in accordance with theCONSORT statement revised recommendations [11].From December 2005 to January 2007, we performed a

randomized, double-blind, dose-dependent parallel-groupsstudy with 160 consecutive adult patients undergoing elec-tive CPB, in a 24-bed intensive care unit (ICU) at a univer-sity hospital.Exclusion criteria included: no informed consent, age <

18 years, emergencies, off-pump cardiac surgery, chroniccoagulopathy (prothrombin time [PT] 2 and platelets 2 mg/dL), gross hematuria, TA hypersensibility, chronichepatopathy (Child-B or higher), immunosuppression,endocarditis and post-operative sepsis within 24 h.Before CPB, all participants had normal bleeding time,

platelet collagen/epinephrine and collagen/ADP closuretime, PT, activated partial thromboplastin time, and

thrombin time. No patients received anti-inflammatoryor immunosuppressive agents during 5 days before and24 h post-CPB.After obtaining written informed consent, the surgeon

requested treatment group assignment immediatelybefore CPB.

TA dosing scheduleDosing schedules for prophylactic TA varies greatly[12,13]. In our center, the TA dosing schedule is an initialbolus (25 mg/Kg) before CPB and another (25 mg/Kg)after completion of CPB. Our first study dealing with TAversus placebo was carried out using this schedule, whichhas demonstrated its effectiveness in relation to bleedingand IR [6]. Given the half-life of TA (80 min), the initialdose inhibits intra-operative fibrinolysis and bleeding. Aloading dose higher than 30 mg/Kg assures a 98-100%reduction of tissue activator activity [14]. Thus the doseschedule used in our study ensured complete inhibitionof fibrinolysis during and early postoperative period afterCPB, although no pharmacokinetic information wasavailable. With the second dose we wished to investigatethe possible benefit of postoperative inhibition of fibrino-lysis on IR.The patients were randomly assigned, by an independent

pharmacist according to a computer generated randomiza-tion list allocated in the Pharmacology Department, toreceive disguised coded infusions of either TA 40 mg/Kgbefore CPB and placebo after CPB (TA1) or TA 40 mg/Kgbefore and after CPB (TA2) after heparin reversal. Thecode was revealed once recruitment, data collection, andlaboratory analyses were completed.

Anesthetic proceduresAnesthetic procedures were standardized and consisted ofan opioid-based anesthetic supplemented with volatileanesthetic and muscle relaxants. All interventions wereperformed by the same surgical team with wide experiencein these surgical interventions. All patients were preopera-tively monitored with a pulmonary artery continuous ther-modilution catheter (Edwards Lifesciences LLC, Irvine,CA, USA). Neither heparin-coated circuits nor leukocytefilters were used. The extracorporeal circuit consisted of ahardshell membrane oxygenator (Optima XP; Cobe, Den-ver, CO, USA, or Quantum Lifestream International, Inc.,Woodlands, TX, USA), a Tygon™ (Dideco s.r.l., Miran-dola, Italy) extracorporeal circuit, and a Medtronic™ Bio-pump (Medtronic, Inc., Minneapolis, MN, USA)centrifugal pump. Below hypothermic temperatures of28°C to 30°C, the pump flow was adjusted to maintain amean arterial pressure of greater than 60 mm Hg and aflow index of 2.2 L/minute per square meter. Myocardialprotection was achieved using antegrade, cold, St. Thomas4:1 sanguineous cardioplegia. The circuit was primed with


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30 mg of heparin followed by an initial dose of 3 mg/kgand further doses when necessary to achieve and maintainan activated clotting time of 480 seconds. To reverse theeffect of heparin, protamine was used based on bloodheparin levels measured by Hepcon® (Medtronic, Inc.). Ablood salvage device (Cobe BRAT2™, Cobe Cardiovascu-lar Inc.TX. USA) was used in all patients. The transfusiontrigger was a hemoglobin threshold of less than 8 g/dL, PTof less than 50%, and platelets of less than 50,000/mm3.Fluid management was carried out to achieve 8 to 12 mmHg of central venous pressure or 12 to 15 mm Hg ofpulmonary artery occlusion pressure at zero positive end-expiratory pressure by infusions of crystalloids and col-loids. Following our routine practice, we used RingerLactate or Saline 0.9% in the intra-operative period. Afterpatient admission to ICU, crystalloids were mainly usedand when colloids were infused we most commonly usedHES 130/0.4 (Voluven ®), not exceeding 1000 ml in24hours.Catecholamine support, when necessary, was used as

follows: Norepinephrine was titrated to achieve a meanarterial pressure of greater or equal to 70 mm Hg, anddobutamine was titrated to achieve a cardiac index ofgreater or equal to2.5 L/minute per square meter.Amines were tapered off in steps of 0.02 and 1 μg/kgper minute, respectively.

Concurrent validationWe validated the clinical criteria of IR and found signifi-cant differences in evolutionary levels of IL-6 in patientswho developed IR versus those without.

Data collectionDemographic variables, comorbidity, perioperative clinicaldata, and postoperative IR, mechanical ventilation time,ICU and hospital stay, and mortality, were recorded. Corebody temperature, laboratory data (hematology, inflamma-tion, coagulation, and fibrinolysis), and hemodynamicparameters were recorded before intervention (baseline),on ICU admission after surgery (0 h), and at 4 h and 24 hpost-CPB, once hemodynamic stability was confirmed. IRwas clinically defined as core body temperature >38°C(100.4°F), systemic vascular resistance index 3.5 L/minute per m2

at 4 h, as we reported in a previous study [6]. We alsorecorded blood loss (chest-tube drainage and hemoderiva-tives) at the above time points and on chest tubes removal.In cases of reintervention due to bleeding, the post-hocclassification of bleeding into “surgical” and “non-surgical”was applied to distinguish between bleeding due tomechanical-surgical causes (where pharmacological mea-sures are not effective) and coagulopathy (which TA wasexpected to reduce). Surgical risk was calculated by Euro-score and Parsonnet score.

Cerebrovascular events included seizure and stroke.Acute kidney injury was assessed applying RIFLE [15] cri-teria (>100% creatinine increase, using preoperative andhighest creatinine concentration during the first weekafter surgery); renal failure was defined as dysfunctionrequiring dialysis. Myocardial infarction was considered aseither new Q waves or new, persistent ST-segment or T-wave changes. Indication for re-operation was determinedby clinical judgment and blood loss as >200 mL/h in threeconsecutive hours. Mortality was defined as death within30 days of CPB, recorded in medical history or telephonecontact with the surgeon responsible or family. Theseadverse effects were included as a composite variable.

Cytokine levelsIL-6 (normal range:

variables were previously log-transformed to ensure nor-mal distribution and homoscedasticity.All preoperative variables showing a P value < 0.15 in

the bivariate analysis (hypertension, post-CPB tempera-ture, total protamine dose) were entered in a multivari-ate binary logistic regression analysis, for categoricalprimary end-point outcome (IR).Mixed ANOVA was used to compare means between

groups in clinical signs (bleeding) and laboratory para-meters (D-dimer, creatine kinase and troponin I) at base-line, 4 h and 24 h after surgery. For bleeding and D-dimer,correction for multiple variables was not carried out in theomnibus test because of the a priori known unidirectionalnature of the effects of TA on these parameters. However,any isolated values in repeated measures were consideredsignificant when P < 0.018, after applying Bonferroni cor-rection. In the case of 24 h bleeding, this was adjusted forsurgery-related bleeding.To test the effect of TA on 24 h postoperative norepi-

nephrine requirements, the statistical analysis includedadjustment for the use of dobutamine. After applyingBonferroni correction, differences with a P value of <0.018 were considered significant.Bivariate associations between IL-6 and D-dimer,

chest-tube bleeding, norepinephrine dose, temperature,troponin I (TnI), creatine kinase (CK), MB isoenzymecreatine kinase (CK-MB) and blood pressure wereassessed using Spearman’s rho coefficient.Qualitative variables are expressed as frequencies and

percentages and quantitative variables as mean and 95%confidence interval (CI), or median and interquartilerange. P values of < 0.05 were considered significant.SPSS 15.0.1 (SPSS Inc. Chicago, IL. USA) and Statistica8.0 (StatSoft, Tulsa, OK) were used.

ResultsFrom December 2005 to January 2007, we recruited 209consecutive CPB patients; 49 were excluded (20 off-pump,4 coagulation disorders, 11 emergencies, 6 endocarditis, 4hemodialysis, and 4 immunosuppressed). Thus we studied160 patients, 80 receiving single-dose TA before CPB and80 receiving TA before and after CPB. Figure 1 shows aflow chart of patients enrolled.Demographic variables, comorbidity, medical treat-

ment, preoperative biochemical data, and surgical proce-dures were similar in the two groups, except for post-CPB temperature and total protamine dose (Table 1).Patients developing IR showed significantly higher

levels of IL-6 at 4 hours postoperatively than those with-out IR, [F (2, 274) = 5.08; P = 0.013], (Figure 2).The incident rate of IR was significantly lower in TA2

(7.5%) than in TA1 (18.8%) (P = 0.030). TA2 showed OR0.29 (95%CI: 0.10-0.83), (P = 0.013) after adjusting forhypertension, total protamine dose and temperature after

CPB. Compared with TA2, the relative risk of IR was 2.5for TA1 (95% CI 1.02-6.12). The absolute risk differencewas 11.3%. The number needed to treat with TA2 toreduce IR was 9 patients (95% CI: 5-107 patients).In the omnibus test TA2 had significantly lower chest-

tube bleeding (P = 0.014). Comparing both groups forchest bleeding at 24 hours, TA2 had lower bleeding thanTA1 [978 (95% CI: 809-1147) vs 1198 (95%CI: 1017-1380)mL; P = 0.010, corrected-P significant], which remainedsignificant after adjusting for surgery-related bleeding (P =0.014, corrected-P significant). On summing intraoperativeand 24 h postoperative bleeding, the effect of TA2 was sig-nificant: [1341 (95% CI: 1197-1486) vs 1538 (95%CI: 1391-1686) mL; P = 0.016, corrected-P significant]. Also in theomnibus test, TA2 had significantly lower D-dimer (P =0.038) than TA1 (Figure 3). TA2 had lower D-dimer levelsat 24 hours [489 (95% CI: 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01, corrected-P significant].TA2 showed significant reduction of maximum CPK

values [407(95%CI: 259-671) vs 487(95%CI: 359-812)U/L; P = 0.01] and TnI [2.6(95%CI: 1.7-4.7) vs 3.6(95%CI:2.7-6.3)U/L; P > 0.01]. TA2 required lower levels of nor-epinephrine at 24 h [0.06 (95%CI: 0.03-0.09) vs 0.20(95CI5%:0.05-0.35), P = 0.03, adjusted for dobutamine[F(1.40) = 6.6; P = 0.014, corrected-P significant].No differences were found in hemoderivative require-

ments or other parameters (Table 2).We found a direct relationship between IL-6 at ICU arri-

val and: temperature (rho = 0.26; P < 0.01), D-dimer (rho= 0.24; P < 0.01), norepinephrine (rho = 0.33; P < 0.01),TnI (rho = 0.37; P < 0.01), CK(rho = 0.37; P < 0.01), CK-MB(rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P <0.01) at arrival. Similarly, a direct correlation was observedbetween IL-6 at 4 h with temperature (rho = 0.23; P <0.01), norepinephrine (rho = 0.25; P < 0.01), TnI (rho =0.42; P < 0.01) and lactic acid (rho = 0.19; P = 0.03) at 4 hand chest tube bleeding at 24 h (rho = 0.18; P = 0.03) andat chest-tube withdrawal (rho = 0.20; P = 0.02), and aninverse relationship with systolic blood pressure at 4 h(rho = -0.17; P = 0.05).Seizure was present in 2 (1.3%) and stroke in 3 (1.9%)

patients. Acute kidney injury occurred in 14 (8.8%)patients, and 7(4.4%) needed dialysis. Finally, 3 (1.9%)suffered myocardial infarction. Seven patients requiredre-operation for bleeding: 5 in TA1 and 2 in TA2,(P =0.44). There were 9 deaths, without significant differencesbetween groups: 3 (3.8%) in TA1 versus 6 (7.6%) in TA2(P = 0.29). Statistically, there were no significant differ-ences in expected vs. observed mortality between the twogroups. According to logistic Euroscore, the rates of mor-tality were: TA1-observed = 3.8% (3/80) and TA1-expected = 3.25% (3/80), (P = 0.99) and TA2-observed =7.6% (6/80)] and TA2-expected = 3.27% (3/80), (P =0.11). There were no significant differences between


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groups in cerebrovascular events, renal pathology, myo-cardial infarction, mechanical ventilation or ICU stayafter surgery, nor when comparing composite adverseeffects (Table 2).

DiscussionThe clinical definition of IR based primarily on earlyhyperthermia with a hyperdynamic state is accompaniedby higher levels of IL-6 at 4 h than in other patients.Peak levels of this interleukin is observed in these firsthours of the postoperative period, as found by our teamin a previous study [6] and by others [16,17]. The pre-sence of hyperthermia in the criteria used avoids thepotential confounding effect of vasoactive drugs on theassociated hyperdynamic state.

Our findings indicate that prolonged inhibition offibrinolysis by a postoperative dose of TA reduces IRand bleeding in CPB patients. TA1 patients presentedhigher levels of D-dimer, greater bleeding and IR thanTA2 patients who received a second dose after CPB.Several mechanisms have been proposed to explain IR

after CPB, including contact activation, ischemia-reperfu-sion, and endotoxemia. These triggers may activate numer-ous systems involving complement, cytokines, immunecellular response and coagulation-fibrinolytic cascades [4].These systems are closely interconnected and providecontinuous feedback, so the release of cytokines[18] oractivation of the complement system [19] may amplify the-fibrinolytic response. This in turn may re-activate therelease of inflammatory mediators by plasmin and

Figure 1 Randomized control trial flow diagram.


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D-dimer [3,20,21]. This amplified IR is especially relevantin CPB.In a previous study, we observed significantly higher

levels of IL-6 in patients with IR and TA was effective inreducing this response [6]. Thus in the present study wefocused on IL-6 and fibrinolysis. In addition to the feed-back between the release of inflammatory markers andfibrinolysis, other components must be considered in therelease of these markers. After CPB (Figure 2) we observeda clear increase in the levels of IL-6 and other interleukins,which interact with each other [16,17] and are involved inproducing fever ("postperfusion syndrome”) [22]. Also,oxidative stress induced by norepinephrine may releaseIL-6 in other settings [23]. In this study, we observed no

differences in IL-6 levels between groups, probablybecause both them received antifibrinolytic.Proinflammatory cytokines may contribute to inflamma-

tory response, myocardial ischemia-reperfusión injury andhemodynamic instability after clinical CPB. This myocar-dial dysfunction has been highlighted in diverse studiesthrough the association between cytokine levels (IL-6) andmarkers of myocardial tissue damage such as TnI y CK[24,25]In the present study, patients developing IR showed

higher levels of IL-6 than those who did not, togetherwith worse hemodynamic status. The associationbetween greater cytokine (IL-6) release, activation offibrinolysis (D-dimer), higher temperature, higher levels

Table 1 Baseline characteristics of treatment groups

Tranexamic acid P

TA1 group(40-0 mg/Kg)

(n = 80)

TA2 group40-40 mg/Kg

(n = 80)

Demographics

Age (years) 65 (62-69) 68 (65-70) 0.24

Male sex, n (%) 54 (67.5) 49 (61.3) 0.41

Parsonnet 9.2 (7.2-11.2) 10.5 (8.4-12.5) 0.30

Euroscorea 4 (3-6) 4 (3-7) 0.38

Logistic Euroscorea 3.25(1.83-5.53) 3.27(1.75-6.68) 0.84

Body mass index (Kg/m2) 28.2 (27.4-29) 27.7 (26.6-28.8) 0.50

Comorbidity

Hypertension, n (%) 43 (53.8) 53 (66.3) 0.11

Diabetes, n (%) 36 (45) 28 (35) 0.42

Medical treatment

Angiotensin-converting enzyme inhibitors, n (%) 28 (35) 22 (27.5) 0.31

Preoperative parameters

Platelet count (× 103 ml-1) 247 (227-267) 262 (239-285) 0.48

D-dimer (ng/ml) 347 (217-476) 287 (221-353) 0.95

International normalized ratio 1.04 (1-1.07) 1.05 (1.01-1.09) 0.28

Cardiac intervention

Coronary, n (%) 45 (56.3) 39 (48.8) 0.51

Valvular, n (%) 25 (31.3) 31 (38.8)

Both, n (%) 9 (11.3) 7 (8.8)

Other, n (%)b 1 (1.3) 3 (3.8)

Second intervention, n (%) 4 (5) 3 (3.8) 0.51

Surgical data

Temperature during cardiopulmonary bypass (°C) 32.3 (32-32.5) 32.3 (32.1-32.5) 0.78

Aortic clamp time (min) 53 (49-58) 51 (46-57) 0.61

Cardiopulmonary bypass time(min) 88 (82-94) 84 (77-92) 0.45

Temperature after cardiopulmonary bypass (°C) 35.5 (35.3-35.6) 35.7 (35.5-35.8) 0.03

Total heparin dose (UI/Kg) 391 (371-412) 400 (379-421) 0.56

Total protamine dose (mg/Kg) 2.7 (2.6-2.8) 2.9 (2.8-3.1) 0.04

Heparine/protamine 1.45 (1.37-1.53) 1.39 (1.33-1.44) 0.29

Blood salvage (ml) 724 (663-784) 703 (636-767) 0.64

Values expressed as mean and 95% confidence interval; frequencies and percentages; amedian and percentiles.bInter-atrial communication.


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of TnI, CK, CK-MB, and increased hemodynamicinstability (norepinephrine requirements and higher lac-tate levels) in the immediate postoperative period sup-port the inter-relation between inflammation andfibrinolysis [18-20].

The protective effect of TA regarding IR, more evidentin the TA2 group, was also reflected in less postopera-tive myocardial tissue damage.Optimal use of inotropes or vasopressors in the perio-

perative period of cardiac surgery remains controversial.

Figure 2 Mixed ANOVA showing the relationship between IR and IL-6 during the follow up.

Figure 3 Mixed ANOVA showing the relationship between Tranexamic acid doses and D-Dimer during the follow up.


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We usually employ a combination of dobutamine plusnorepinephrine in patients who develop postoperativecardiac dysfunction when there is associated hypoten-sion, to maintain an adequate perfusion pressure. Thiswould justify the use of norepinephrine in patients whodo not develop IR [26,27]. Although the initial analysis

revealed no differences in the need for norepinephrinein the first 24 hours postoperatively between the treat-ment groups, differences did appear at 24 h after adjust-ing for the dose of dobutamine at the time.Although TA effectively reduces bleeding after cardiac

surgery, doses vary widely [12,13]. Most are based on an

Table 2 Outcomes of treatment groups

Tranexamic acid P


(n = 80)


(n = 80)

D-dimer (ng/mL) 0-h 363 (307-420) 311 (257-365) 0.038*

D-dimer (ng/mL) 4-h 416 (376-455) 283 (254-312)

D-dimer (ng/mL) 24-ha 621 (563-679) 489 (437-540)

Chest tube bleeding (cc) 0 h 136 (109-163) 109 (89-129) 0.014†

Chest tube bleeding (cc) 4 h 366 (282-449) 263 (222-304)

Chest tube bleeding (cc) 24 hb 826 (704-949) 671 (549-793)

Chest tube total bleeding (cc) 1198 (1017-1380) 978 (809-1147)

Transfused patients at 24 h (%) 22 (27.8) 19 (23.8) 0.55

Inflammatory response (%) 15 (18.8) 6 (7.5) 0.03

Temperature > 38 (°C) n(%) 15(18.8) 6(7.5) 0.03

Cardiac index > 3.5 (L/min/m2) n(%) 65(82.3) 58(75.3) 0.29

Systemic vascular resistance index

initial dose and subsequent infusion, which can result inhigh cumulative doses. TA half-life is 80 min, and theeffect of a single dose (TA1) is nearly 100% inhibition ofplasmin activity[14] in the immediate postoperative per-iod, so a second dose administered at the end of surgerymay prevent IR and bleeding complications, sinceenhanced fibrinolysis might be expected after heparinreversal [28].Thus the dosing schedule used in our study ensures

complete inhibition of fibrinolysis, although no pharma-cokinetic information was available. With the seconddose we wished to investigate the possible benefit ofpostoperative inhibition of fibrinolysis on IR.It is questionable whether the statistically smaller

blood loss in TA2 group is really clinically relevant, interms of transfusion requirements. The use of hemoder-ivatives partly depends on the transfusion policy of eachcenter, as in our case. However, given that numerousauthors concur on the need for antifibrinolytic agents incardiac surgery [29], we believe the protective effect ofthe TA2 dosing schedule used in the present study onIR and clinical parameters should be considered.The incidence of non-ischemic clinical seizure varies

from 2.7% to 4.6% in most major surgical procedures[8-10], only 0.4% in CABG [9], but as high as 6.7% [8]or 7.9% [9] in open chamber surgery. This adverse effecthas been reported with different several dosing sche-dules and cumulative doses of 61-259 mg/kg [8-10].The incidence of non-ischemic clinical seizure was 0%

in the single-dose group versus 2.5% in the double-dosegroup (non-significant difference); one patient under-went CABG and the other open chamber surgery (valvereplacement), and both had associated renal dysfunction.Although our incidence was below the limits reportedby other authors, with slightly higher cumulative dosesthan those used by Martin K et al [9] and lower thanSander M et al [8] and Murkin JM et al [10], thereseems to be a certain dose-dependent relationship withseizure.Tranexamic acid has been shown to have an epilepto-

genic effect in animals [30]. The suspected mechanismis a g-aminobutiric acid-driven inhibition of the centralnervous system [31]. The patho-mechanism of the twoseizures recorded in our study remains undetermined.Both occurred in patients with postoperative renal dys-function which facilitates accumulation of the drug, andone patient underwent aortic valve surgery wheremicro-plaque dislodgement or the presence of micobbu-bles, which inevitably remain after closing the heart,could have triggered the seizure. This may also partlyexplain the higher incidence of seizure in open chambersurgeryCerebrovascular events, renal pathology and myocar-

dial infarction were similar to those reported previously

[32]. Hospitalization and mortality were similar in bothgroups.

LimitationsWith 80 patients in each group, we empirically estimateda 13% difference between the incidence rates of IR,because in the balance between safety and effectiveness,we preferred safety. Although the empirical power for theobserved proportions (18.8 vs. 7.5) was 67%, the studywas sufficiently powered and significant differences werefound at the end of the study.Although the incidence of adverse events observed are

consistent with that reported in other series, the studywas underpowered to be able to affirm that the dosingschedule was safe since the sample size was calculatedfor IR.Only IL-6 was measured as a biochemical marker of

inflammatory response to CPB. However, this cytokineis widely used in this context, as shown in theliterature [16,17].Blood levels of TA were not measured, but the phar-

macokinetic profile of this drug has been previously stu-died by other authours and the dosing schedule wasbased on their findings [14].Lastly, the experimental nature of this single-center

study with CPB patients undergoing a particular surgicaltechnique (with non-coated circuits), limits the externalvalidity of our findings.

ConclusionsIn conclusion, an additional postoperative dose of TAmay reduce IR and postoperative bleeding (but nottransfusion requirements) in CPB patients. A questionwhich remains unanswered is whether the dose usedwas ideal in terms of safety, but in terms of effectivenesswe have no doubt

List of abbreviationsCPB: Cardiopulmonary bypass; TA: Tranexamic acid; IR: Inflammatoryresponse; MOF: Multiorganic organ failure; ICU: Intensive care unit; PT:Prothrombin time; IL-6: Interleukin-6

AcknowledgementsThe authors wish to thank the following people: all the Nursing personnel ofthe Intensive Care Unit, Hospital Universitario de Canarias for theircollaboration, and Michael McLean for help with the English version of themanuscript.

Author details1Critical Care Department. Hospital Universitario de Canarias. Ofra s/n, LaCuesta. 38320-La Laguna. España. 2Nephrology Department. HospitalUniversitario Carlos Haya, 29010-Málaga. España. 3Mixed Research Unit.Hospital Universitario de Canarias. Ofra s/n, La Cuesta. 38320-La Laguna.España. 4Hematology Laboratory. Hospital Universitario de Canarias. Ofra s/n,La Cuesta. 38320-La Laguna. España. 5Biochemical laboratory. HospitalUniversitario de Canarias. Ofra s/n, La Cuesta. 38320-La Laguna. España.6Cardiac Surgery Department. Hospital Universitario de Canarias. Ofra s/n, LaCuesta. 38320-La Laguna. Tenerife. España.


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Authors’ contributionsJJJ and JLI were responsible for the study design, data collection, processingblood samples during the study, statistical analysis, data interpretation, anddrafting the manuscript. DH, AJ were responsible for the statistical analysis,data interpretation, and drafting the manuscript. MB, LL, RP and MLM, wereresponsible for data collection and processing blood simples during thestudy and provided useful suggestions. PM and JMR, was responsible fordetermination of coagulation-fibrinolysis parameters and interpretation. JMBand BM, was responsible for determination of IL-6 and interpretation. RMwas the surgical team and was responsible for preoperative clinical andanalytical data collection. All authors read and approved the finalmanuscript.

Competing interestsThe authors declare that they have no competing interests.

Received: 6 July 2011 Accepted: 14 October 2011Published: 14 October 2011

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doi:10.1186/1749-8090-6-138Cite this article as: Jiménez et al.: Safety and Effectiveness of twotreatment regimes with tranexamic acid to minimize inflammatoryresponse in elective cardiopulmonary bypass patients: a randomizeddouble-blind, dose-dependent, phase IV clinical trial. Journal ofCardiothoracic Surgery 2011 6:138.


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AbstractBackgroundMethodsResultsConclusionsCurrent Controlled Trials number

BackgroundMethodsTA dosing scheduleAnesthetic proceduresConcurrent validation

Data collectionCytokine levelsCoagulation and fibrinolysis determinationStatistical analysisSample size

ResultsDiscussionLimitationsConclusionsAcknowledgementsAuthor detailsAuthors' contributionsCompeting interestsReferences

research article open access safety and effectiveness ......in vitro studies suggest that the...

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